. PROJECT SUMMARY ABSTRACT In the current application, PEI-PEG-RGD targeted gene carrier was synthesized and characterized. The constructed plasmid encoding sFllt-1 was carried to angiogenic dermal microvascular endothelial cells. The in vivo studies demonstrated that expressed sFlt-1 carried by this delivery system delayed tumor growth and increased survival rate of animal. Therefore, PEI-PEG-RGD/pCMV- sFlt-1 complex can be useful to develop tumor specific anti-angiogenic gene therapy. In addition, combination of IL-2 and sFlk-1 plasmid was constructed. The in vitro and in vivo studies demonstrated excellent efficiency of anti-tumor activity. In this renewal application, we propose to deliver siRNA for silencing VEGF and VEGF receptors. RGD will be conjugated to the reducible polymer, poly (CBA-DAH), which is known to be non-toxic and greatly enhances transfection in several cell lines. RGD-chol-R9C will also be synthesized, since chol-R9C has demonstrated high transfection of siRNA. In addition, RGD- PEG-water soluble lipopolymer (WSLP) will be designed as WSLP has been proven an excellent carrier in this laboratory. Extensive in vitro and in vivo animal studies will be carried out with these RGD-conjugated polymers complexed with siRNA. Inhibition of tumor growth in murine prostate and breast adenocarcinoma models will be proven in the results. The obtained data can be utilized for the design of siRNA delivery to treat cancer patients. PUBLIC HEALTH RELEVANCE: Three newly designed polymers will be conjugated with RGD. It is expected that both in vitro and in vivo studies will present positive results for siRNA delivery, which can be applied to tumor treatment.